tbuckley/cabot-search huggingface dataset:
Abstract 4170: Integrative transcriptomic and proteomic analysis reveals immunogenic and spatially-conserved HLA-binding neoantigen targets derived from tumor-specific alternative splicing events
Authors: Darwin Kwok, Takahide Nejo, Aidan Du, Maggie Colton, James Woo, Joseph Costello, Hideho Okada
Journal: Cancer Research (2022)

Abstract BACKGROUND: While immunotherapy is profoundly efficacious in certain cancers, its success is limited in cancers with lower mutational burden, such as gliomas. Therefore, investigating neoantigens beyond those from somatic mutations can expand the repertoire of immunotherapy targets. Recent studies detected alternative-splicing (AS) events in various cancer types that could potentially translate into tumor-specific proteins. Our study investigates AS within glioma to identify novel MHC-I-presented neoantigen targets through an integrative transcriptomic and proteomic computational pipeline, complemented by an extensive spatiotemporal analysis of the AS candidates. METHODS: Bulk RNA-seq of high tumor purity TCGA-GBM/LGG (n=429) were analyzed through a novel systematic pipeline, and tumor-specific splicing junctions (neojunctions) were identified in silico by cross-referencing with bulk RNA-seq of GTEx normal tissue (n=9,166). Two HLA-binding prediction algorithms were subsequently incorporated to predict peptide sequences with high likelihood for HLA-presentation. Investigation of the tumor-wide clonality and temporal stability of the candidates was performed on extensive RNA-seq data from our spatially mapped intratumoral samples and longitudinally collected tumor tissue RNA-seq. Proteomic validation was conducted through mass-spec analysis of the Clinical Proteomic Tumor Analysis Consortium (CPTAC)-GBM repository (n=99). RESULTS: Our analysis of TCGA-GBM/LGG bulk RNA-seq identified 249 putative neojunctions that translate into 222 cancer-specific peptide sequences which confer 21,489 tumor-specific n-mers (8-11 amino acids in length). Both prediction algorithms concurrently identified 271 n-mers likely to bind and be presented by HLA*A0101, HLA*A0201, HLA*A0301, HLA*A1101, or HLA*A2402. We confirmed the expression of 15 out of 58 HLA*A0201-binding candidates in RNA-seq of two HLA*A0201+ patient-derived glioma cell lines with a subset of candidates found tumor-wide. Analysis of CPTAC-GBM mass-spec data detected 23 tumor-specific peptides with 5 containing detected n-mers highly predicted to be HLA-presented. CONCLUSION: Tumor-specific neojunctions identified in our unique integrative pipeline present novel candidate immunotherapy targets for gliomas and offer a new avenue in neoantigen discovery across cancer types. Citation Format: Darwin Kwok, Takahide Nejo, Aidan Du, Maggie Colton, James Woo, Joseph Costello, Hideho Okada. Integrative transcriptomic and proteomic analysis reveals immunogenic and spatially-conserved HLA-binding neoantigen targets derived from tumor-specific alternative splicing events [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4170.
Abstract 5495: PHI-501, a potent and novel inhibitor of <i>NRAS</i> mutated acute myeloid leukemia
Authors: Ky-Youb Nam, Jung Hee Park, Kyung Ah Kim, Inje Shin, June H-J Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Hanna Cho, Seung-Hye Choi, Sandip Sengupta, Taebo Sim
Journal: Cancer Research (2022)

Abstract Purpose: Development of the first-in-class inhibitor of NRAS mutated acute myeloid leukemia. PHI-501 has potent activity against receptor tyrosine kinases and intracellular kinases related to STAT, AKT, and ERK signaling. Description: Preclinical testing of PHI-501 for efficacy against NRAS mutations both in vitro and in vivo xenografts. Summary: Mutations in the RAS genes (including KRAS, NRAS, and HRAS) are discovered in about 30% of all tumors. KRAS is the most frequently mutated gene in cancers found in pancreatic, colon, and lung, while NRAS mutations around the hot spots at codons 12, 13, and 61 are more common in AML (10.3%). PHI-501 is a novel small molecule inhibitor intended for the treatment of AML in patients expressing the N-RAS activating mutation. PHI-501 presented higher selectivity within a panel of 355 protein kinases. PHI-501 exerts their anti-proliferative effects by inducing apoptosis and G0-G1 arrest and significantly induce apoptotic markers (cleaved PARP and caspase 3) in both Ba/F3-NRAS-G12D and OCI-AML3 cells. The results of Western blot analysis showed that PHI-501 attenuate phosphorylation of p70S6K1, AKT, and p38 in OCI-AML3 After 21 days of the treatment in subcutaneous OCI-AML3 human AML xenograft model, PHI-501 showed significant inhibition of tumor growth (TGI) in a dose-dependent manner. Compared to the vehicle group, the 40 mg/kg group demonstrated a 74.0% lower average tumor volume (P&amp;lt;0.0001) and a 78.5% lower average tumor weight (P=0.0041). No significant body weight changes were observed in any of the groups. In toxicology and pharmacokinetic study, PHI-501 exhibited pharmacokinetic profiles favorable for oral administration in rodent, dog, and monkey and displayed acceptable in vivo and in vitro safety profiles. These results show the significant ability of PHI-501 to inhibit the progression of NRAS activated AML tumor growth, making it a strong candidate for the treatment of AML. Conclusion: The preclinical evaluation of PHI-501, a novel N-RAS inhibitor, showed clear evidence of anticancer activity for AML and improved efficacy in both in vitro and in vivo models. Consequently, PHI-501 is a new potent multi-kinase inhibitor with characteristics that warrant entry into human trials for the treatment of AML in patients expressing the N-RAS activating mutation. Citation Format: Ky-Youb Nam, Jung Hee Park, Kyung Ah Kim, Inje Shin, June H-J Han, Kyu-Tae Kim, Jeong Hyeok Yoon, Hanna Cho, Seung-Hye Choi, Sandip Sengupta, Taebo Sim. PHI-501, a potent and novel inhibitor of NRAS mutated acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5495.
Abstract 5207: Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity
Authors: Valeria Lucarini, Ombretta Melaiu, Silvia D'Amico, Fabio Pastorino, Patrizia Tempora, Adele De Ninno, Luca Businaro, Mirco Ponzoni, Franco Locatelli, Doriana Fruci
Journal: Cancer Research (2022)

Abstract Poor infiltration of functioning T cells renders tumors unresponsive to checkpoint-blocking immunotherapies. Here, we employed a combinatorial in situ immunomodulation strategy based on the administration of selected immunogenic drugs and immunotherapy to sensitise two mouse models of neuroblastoma (NB) sparsely infiltrated by T cells to the host antitumor immune response. Using multiple in vitro, ex vivo, and in vivo approaches, we found that mitoxantrone treatment curbed NB growth and promoted tumor regression when combined with TGFβ and PD-1 blockade in aggressive NB models. This combined immunotherapy strategy resulted in the enrichment of a variety of both innate and adaptive immune cells into the TME, and the concomitant production of inflammatory chemokines involved in remodelling the tumor’s immune landscape. Mitoxantrone in combination with TGFβ and PD-1 blockade could be used to reshape the functional repertoire of intratumoral immune cells, restoring the entire immune cell cycle and overcoming the immunosuppressive microenvironment of aggressive NB. Citation Format: Valeria Lucarini, Ombretta Melaiu, Silvia D'Amico, Fabio Pastorino, Patrizia Tempora, Adele De Ninno, Luca Businaro, Mirco Ponzoni, Franco Locatelli, Doriana Fruci. Mitoxantrone in combination with TGFβ and PD-1 blockade remodels the tumor immune landscape enhancing neuroblastoma antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5207.
Mitochondrial H <sub>2</sub> S Regulates BCAA Catabolism in Heart Failure
Authors: Zhen Li, Huijing Xia, Thomas E. Sharp, Kyle B. LaPenna, John W. Elrod, Kevin M. Casin, Ken Liu, John W. Calvert, Vinh Q. Chau, Fadi N. Salloum, Shi Xu, Ming Xian, Noriyuki Nagahara, Traci T. Goodchild, David J. Lefer
Journal: Circulation Research (2022)

Hydrogen sulfide (H2S) exerts mitochondria-specific actions that include the preservation of oxidative phosphorylation, biogenesis, and ATP synthesis, while inhibiting cell death. 3-MST (3-mercaptopyruvate sulfurtransferase) is a mitochondrial H2S-producing enzyme whose functions in the cardiovascular disease are not fully understood. In the current study, we investigated the effects of global 3-MST deficiency in the setting of pressure overload-induced heart failure. Human myocardial samples obtained from patients with heart failure undergoing cardiac surgeries were probed for 3-MST protein expression. 3-MST knockout mice and C57BL/6J wild-type mice were subjected to transverse aortic constriction to induce pressure overload heart failure with reduced ejection fraction. Cardiac structure and function, vascular reactivity, exercise performance, mitochondrial respiration, and ATP synthesis efficiency were assessed. In addition, untargeted metabolomics were utilized to identify key pathways altered by 3-MST deficiency. Myocardial 3-MST was significantly reduced in patients with heart failure compared with nonfailing controls. 3-MST KO mice exhibited increased accumulation of branched-chain amino acids in the myocardium, which was associated with reduced mitochondrial respiration and ATP synthesis, exacerbated cardiac and vascular dysfunction, and worsened exercise performance following transverse aortic constriction. Restoring myocardial branched-chain amino acid catabolism with 3,6-dichlorobenzo1[b]thiophene-2-carboxylic acid (BT2) and administration of a potent H2S donor JK-1 ameliorates the detrimental effects of 3-MST deficiency in heart failure with reduced ejection fraction. Our data suggest that 3-MST derived mitochondrial H2S may play a regulatory role in branched-chain amino acid catabolism and mediate critical cardiovascular protection in heart failure.
One Adrenal Is Worth Two—Reply
Authors: Marco Fiore, Lorenzo Conti, Ettore Seregni
Journal: JAMA Surgery (2022)

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Abstract 2932: The 6-color naica® system: a digital PCR platform and workflow for high multiplex genetic detection and analysis
Authors: Andrew Hoskins, Shekerah Primus, Mary Yazdani, Kimberley Gutierrez, Benjamin Foret, Fabien Bernard, Rémi Dangla
Journal: Cancer Research (2022)

Abstract There are several molecular platforms routinely used to investigate genomic material. Quantitative polymerase chain reaction (qPCR) is ubiquitously used because of the ease of use and the precision however, it does not offer high multiplexing. While digital PCR (dPCR) is known for increased precision and sensitivity, most digital PCR platforms provide the same level of multiplexing as qPCR. Next-generation sequencing (NGS) is less precise than qPCR or dPCR and but has the highest multiplexing capability of the three technologies. Conventional digital PCR systems have been limited by the number of instruments required to conduct the workflow, time-to-result compared to qPCR, and level of multiplexing as compared to next-generation sequencing (NGS). Crystal Digital PCR™ and the naica system is a next-generation digital PCR platform that simplifies the number of instruments in the workflow, speeds up the time of results to less than 3 hours, and increases the number of detection colors to 6 spectrally distinct channels. By using a combination of dual-labelled fluorescent probes, multiplexed digital PCR provides a simple solution that makes it possible to use less of a precious sample when faced with limited quantity without sacrificing sensitivity. The naica system workflow utilizes microfluidic consumables, such as the Sapphire chip for high sensitivity applications, and the Opal chip for higher throughput studies. All reagents including primers and probes, master mix, and sample are inputted into the chips in one single loading step. Chips are transferred to the Geode instrument, where the sample is partitioned into a 2D-monolayer of droplet crystals and where all targets are amplified. After the PCR program has been completed, the same chips are then loaded into the Prism6 imager which detects all targets across 6 fluorescent channels and outputs an image of all droplets in a sample. Finally, Crystal Miner analysis software can be used to analyze and decipher the quantifications and expression of all targets in the assay. The 6-color naica system allows for high multiplex detection of targets previously unattainable by conventional digital PCR systems. With this advent, genomic scientists have an additional platform in the molecular toolbox that supports seamless assay development of oncology biomarker assays for gene expression, rare target detection, and liquid biopsy applications. Citation Format: Andrew Hoskins, Shekerah Primus, Mary Yazdani, Kimberley Gutierrez, Benjamin Foret, Fabien Bernard, Rémi Dangla. The 6-color naica® system: a digital PCR platform and workflow for high multiplex genetic detection and analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2932.
Abstract 417: Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients
Authors: Dong Hyuk Ki, Joonwoo Nam, Eunjung Kim, Hunmi Choi, Chulwon Kim, Jiyeon Kim, Jimmy Jin, Sang-Uk Kang, Wooseok Han
Journal: Cancer Research (2022)

Abstract Although EGFR-targeted tyrosine kinase inhibitors (TKIs) developed over a couple of decades have made great progress in the treatment of EGFR-mutant driven NSCLC, patients are at great risk to their lives due to drug resistance caused by constantly emerging EGFR mutations. Targeted protein degraders (TPDs), also known as heterobifunctional protein degraders or PROteolysis TArgeting Chimeras (PROTACs), have drawn great attention as a new modality to overcome drug resistance by achieving selective degradation of disease-causing proteins, like an EGFR mutant protein, which are required for the survival and proliferation of various malignant tumor cells. Therefore, we have developed a series of EGFR mutant degraders using BBT-176, a 4th generation EGFR TKI developed by Bridge BioTherapeutics, and novel EGFR inhibitors as warheads which are expected not only to treat various EGFR mutated NSCLC including C797S but also to delay drug resistant-mechanisms by further mutations in the EGFR TKI target site. We synthesized a set of heterobifunctional degraders applying Cyrus BiFx Degrader (CBD) library platform containing different types of linkers and E3 ligase binders. DC50 (half-maximal degradation concentrations) values of the EGFR degraders were obtained in multiple human EGFR mutant NSCLC cell lines, where C-2051, C-2482, and C-4383 showed excellent EGFR degradation potency (DC50 = 7-25 nM, Dmax at 100 nM = 80-97%) with high selectivity against WT EGFR. Among those compounds, C-4383 was potent in cell viability assays with EGFR mutant HCC827 (Del19) and NCI-H1975 (L858R, T790M) cell lines showing a range of GI50 values from 77 to 81 nM at 72 h of compound exposure. By contrast, the compound was much less potent in A549 cells harboring wild-type EGFR (GI50 value at 72 h of treatment, 4.2 μM). We also performed proteomic analysis of C-4383 in H1975 cells resulting that EGFR was the most degraded protein with no off-target events at 100 nM (Dmax dose). A PK study of C-4383 in rats showed good exposure with moderate CL when administered intravenously (CL = 8.51 mL/min/kg, AUC = 5911 ng•h/mL). In summary, we identified heterobifunctional degraders using a 4th generation EGFR inhibitor, BBT-176, that are active in EGFR mutant NSCLC cells harboring single or C797S-containing multiple mutations. We are currently making our efforts on the improvement of physicochemical properties of EGFR mutant targeted heterobifunctional compounds. Citation Format: Dong Hyuk Ki, Joonwoo Nam, Eunjung Kim, Hunmi Choi, Chulwon Kim, Jiyeon Kim, Jimmy Jin, Sang-Uk Kang, Wooseok Han. Identification of next-generation EGFR degraders to treat non-small cell lung cancer (NSCLC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 417.
Screening for Glaucoma
Authors: Henry D. Jampel, Aakriti Garg Shukla
Journal: JAMA (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Journals JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 5938: Administering colorectal cancer education via an inflatable colon with the underrepresented and underserved population of Arizona
Authors: Desiree Jones, Gabriela Ruiz, Juan Contreras, Rene D. Herrera, Amanda A. Lee, Monica Yellowhair, Jennifer Hatcher
Journal: Cancer Research (2022)

Abstract Background: The state of Arizona has a diverse population, with the Latino (31.7%) and American Indian/Alaskan Natives (AI/AN) (5.3%) populations higher than the national average of 18.5% and 1.3%, respectively. The colorectal cancer (CRC) screening rates among Latinos is 54.8% and AI/AN is 35%, compared to the overall Arizona screening rate of 62.6%, potentially contributing to higher CRC mortality rates in these groups. Objective: Utilizing an inflatable colon to measuring CRC knowledge and intent to screen among Arizona’s diverse populations by administering a pre/post test. Methods: An inflatable colon with signs in both English and Spanish describes the progression of CRC. Spanish-speaking health educators and culturally tailored flip charts geared toward the AI/AN population are utilized at community events throughout Arizona. Survey distribution measured pre- and post-CRC knowledge and intent to screen following a walking tour of the inflatable colon. Additional efforts include the production of a virtual tour of the giant colon in English and Spanish as an educational tool easily accessible on the UArizona Cancer Center YouTube page. Results: Convenience sampling is utilized, and participants are recruited at outreach events where the inflatable colon is set up (n=15). Preliminary findings show that individuals increased their knowledge about CRC (76.9% vs 100%), understanding the pathology of CRC (i.e., colon polyp, normal colon tissue vs. cancerous tissue, etc.) (53.8% vs 100%), and CRC screening recommendations (30.8% vs 91.7%). Conclusions: Colorectal cancer education is reaching diverse populations in Arizona. CRC education is delivered in both English and Spanish, and additional CRC educational tools such as the culturally tailored colon health flipbook for AI/AN population are utilize. The use of the inflatable colon has increased CRC knowledge, CRC pathology, and CRC screening options. Citation Format: Desiree Jones, Gabriela Ruiz, Juan Contreras, Rene D. Herrera, Amanda A. Lee, Monica Yellowhair, Jennifer Hatcher. Administering colorectal cancer education via an inflatable colon with the underrepresented and underserved population of Arizona [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5938.
Blood trihalomethane concentrations and lung function in US adolescents: a nationally representative cross-sectional study
Authors: Yang Sun, Yi-Xin Wang, Vicente Mustieles, Yu Zhang, Xiong-Fei Pan, Carmen Messerlian
Journal: European Respiratory Journal (2022)

<b>In a representative sample of 1298 United States adolescents, higher blood trihalomethane concentrations were associated with lower lung function parameters and a higher risk of poor lung function</b>https://bit.ly/3sMbP0V
Abstract 3778: Mitochondrial dynamics in cancer restored by a bioactive fraction of fermented wheat germ extract
Authors: Gyula Bencze
Journal: Cancer Research (2022)

Abstract Bioactive fraction of Fermented Wheat Germ Extract (A250) was shown to be effective in increasing gene expression of mitochondrial proteins in a dose-dependent manner. According to the STRING protein network analysis these proteins are linked to the Krebs cycle and apoptosis. However, the in vivo therapy had no effect on the white blood cell count, and the increase in the immune cell profile was favorable, indicating that its effect was specific to tumor cells. Citation Format: Gyula Bencze. Mitochondrial dynamics in cancer restored by a bioactive fraction of fermented wheat germ extract [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3778.